Ovarian cancer is the eighth most common cancer in women, the fifth most common cause of cancer-related death in women and the leading cause of gynecological cancer death. One- and five-year survival is only 76% and 45%, respectively, primarily due to the late stage at diagnosis for most women. While it is clear that exogenous hormones in the form of oral contraceptives (OCs) are associated with decreased risk of epithelial ovarian cancer (ovarian cancer), the situation with the other major form of exogenous hormone use, namely, menopausal hormone therapy (HT) is less clear. We have recently shown that while duration of estrogen therapy (ET) use is clearly associated with increased risk of ovarian cancer, estrogen plus progestin therapy (EPT) is associated with a statistically significant lower risk than ET. This observation brings to light fundamental questions with regard to the etiology of ovarian cancer: If a progestin can ameliorate some of the risk-inducing properties of estrogen, what effect does a larger progestin dose have and does dose scheduling matter? And, if it is true that progestins can block the effect of estrogen on ovarian cancer risk it might suggest that the mechanism through which both OCs and pregnancy, both of which create higher than normal exposure to progestins, decrease risk is not through blocking ovulation, but rather through the increased progestin exposure. Also relevant is whether these effects differ based on histological subtype of the tumor, recency of use, or presence of other risk factors such as obesity. These questions need to be answered. In addition to HT, there are several additional suspected/known risk factors which are in need of further follow-up: endometriosis, infertility and hysterectomy. The relationship between risk of ovarian cancer and specific parameters of these exposures (e.g., timing of endometriosis, reasons for infertility, timing of hysterectomy), environmental modifiers of the association (e.g., history of OC use), and tumor characteristics needs to be addressed. Historically these would have been very difficult analyses to undertake because individual studies are not adequately powered, but members of the Ovarian Cancer Association Consortium (OCAC) have recognized the need to work collaboratively to pool data to address such questions. Fifteen groups from around the world have agreed to contribute data on more than 13,000 ovarian cancer cases and 17,000 healthy controls to comprehensively address the role of HT, endometriosis, infertility and hysterectomy with ovarian cancer risk in order to shed light on the etiology of the disease. Importantly, because the infrastructure of the OCAC has already been established and the investigators have a track record of working together this work can be conducted efficiently and cost-effectively. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the eighth most common cancer in women, the fifth most common cause of cancer-related death in women and the leading cause of gynecological cancer death;one- and five-year survival is a paltry 76% and 45%, respectively. We will conduct pooled analyses of existing data using data from 15 groups from around on the world on more than 13,000 ovarian cancer cases and 17,000 healthy women to answer questions about risk of ovarian cancer and the following exposures of interest: menopausal hormone therapy, endometriosis, infertility and hysterectomy. Gaining a better understanding of ovarian cancer, which this project will provide, is critical to identifying women at risk and for improving the outcome for women who are diagnosed with this disease.